JP6595509B2 - N-sulfonylhomoserine lactone derivative, process for its preparation and use - Google Patents

Description

TECHNICAL FIELD The present invention belongs to the pharmaceutical and chemical industry fields, and in particular, relates to N-sulfonylhomoserine lactone derivatives, methods for their preparation, and their use in the manufacture of a medicament for the prevention and / or treatment of diseases caused by gram-negative bacteria.

Background Art During an increase in cell density, bacteria can continually produce chemical signaling molecules (also called autoinducers), which are then secreted into the extracellular environment. When the concentration of signaling molecules reaches a threshold, the expression of bacterial related genes such as bioluminescence, biofilm formation and pathogenicity related genes is regulated or activated to adapt to environmental changes. Such a regulatory system is known as a bacterial quorum sensing (QS) system.

  The QS system is First observed in V. fischeri. When the density of bacteria is high, the bacteria emit light to catch food and avoid predators. By studying the mechanism, V. In Fischery, N-acyl homoserine lactone (AHL) synthesized by LuxI protein binds to the NHL terminus of AHL receptor protein encoded by LuxR and allows binding of the C-terminus of AHL receptor protein to the target DNA sequence It has been found that a specific configuration can be formed, thereby activating transcription and expression of the luminescent gene. Similar regulatory systems have been found in many gram positive or gram negative bacteria. Their mechanism is that when bacteria are of low population density, little autoinducer is produced, and that inducer diffuses out of the cell and is immediately diluted in the surrounding environment. When the bacterial population density gradually increases and reaches a threshold, the signaling molecule penetrates into the cell and binds to the corresponding transcriptional regulatory protein, a specific DNA encoding the signaling molecule in the chromosome It forms a transcriptional regulatory protein-signaling molecule polymer that can bind to the sequence and allow the expression of the associated target gene, resulting in the production of more signaling molecules. Such communication and transmission of information between bacteria has been proposed for a long time. However, systematic research has only been conducted in the last decade. Such a phenomenon has now been demonstrated in many bacteria.

  In the late 1970s, scientists discovered that naturally occurring or artificially synthesized cell density sensing regulators (including agonists or inhibitors) interfered with signal transduction system transmission and reduced the expression of virulence genes in bacteria. I found that it can be adjusted. Cell density sensing regulators deprive pathogenic bacteria from pathogenic bacteria by modulating the expression of their virulence genes without interfering with the normal physiological functions of cells in vivo. Therefore, it is considered a new direction for the development of antibacterial agents. Bacterial density sensing inhibitors can be used in combination with antibiotics to enhance the susceptibility of pathogenic bacteria to antibiotics to improve the therapeutic effect of the drug, and various caused by gram-negative bacteria Can be used to treat various diseases such as endocarditis, peritonitis, gastroenteritis, cholecystitis, cystitis, diarrhea, empyema, and sepsis.

  The object of the present invention is to find a novel cell density sensing control agent for use in the prevention and / or treatment of diseases caused by gram-negative bacteria, particularly diseases caused by drug-resistant gram-negative bacteria.

In a first aspect, the present invention provides compounds of formula I

Wherein R is a group selected from heteroaryl and benzyl, optionally, the group is mono-substituted by a substituent selected from the group consisting of halogen, trifluoromethyl, nitro, and C _1-6 alkyl Or polysubstituted (eg, disubstituted or trisubstituted)
Homoserine lactone derivatives thereof, or racemic or optical isomers, pharmaceutically acceptable salts, solvates, or hydrates thereof.

For the homoserine lactone derivative according to the first aspect of the invention, or its racemate or optical isomer, pharmaceutically acceptable salt, solvate or hydrate, preferably R is thienyl, furyl , Pyrrolyl, pyridyl and benzyl, optionally the group is mono- or poly-substituted (eg di-substituted) by substituents selected from halogen, trifluoromethyl, nitro, and C _1-6 alkyl. Substituted or trisubstituted).

In some embodiments of the invention, R is thienyl, optionally wherein the thienyl is monosubstituted with a substituent selected from halogen, nitro, and C _1-6 alkyl.

In some embodiments of the invention, R is furyl, and optionally the furyl is monosubstituted by a substituent selected from halogen, nitro, and C _1-6 alkyl, or by halogen. Disubstituted.

  In some embodiments of the invention, R is pyrrolyl.

  In some embodiments of the invention, R is pyridyl.

In some embodiments of the invention, R is benzyl, optionally where the benzyl is monosubstituted with a substituent selected from halogen, nitro, C _1-6 alkyl and trifluoromethyl, or by halogen. Disubstituted.

  For the homoserine lactone derivative according to the first aspect of the invention, or its racemic or optical isomer, pharmaceutically acceptable salt, solvate or hydrate, preferably R is thienyl, Chlorothienyl, bromothienyl, nitrothienyl, methylthienyl, furyl, nitrofuryl, bromofuryl, methylfuryl, dibromofuryl, pyrrolyl, pyridyl, chloropyridyl, fluorobenzyl, chlorobenzyl, bromobenzyl, methylbenzyl, trifluoromethylbenzyl, nitro Selected from the group consisting of benzyl and dichlorobenzyl.

For the homoserine lactone derivative according to the first aspect of the present invention, or its racemic or optical isomer, pharmaceutically acceptable salt, solvate, or hydrate, preferably the homoserine lactone derivative is ,Less than:
(S) -N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) thiophene-2-carboxamide (Compound 1);
(S) -N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) thiophene-3-carboxamide (Compound 2);
(S) -5-chloro-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) thiophene-2-carboxamide (Compound 3);
(S) -5-bromo-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) thiophene-2-carboxamide (Compound 4);
(S) -5-nitro-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) thiophene-2-carboxamide (Compound 5);
(S) -4-Bromo-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) thiophene-2-carboxamide (Compound 6);
(S) -4-Methyl-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) thiophene-2-carboxamide (Compound 7);
(S) -3-Methyl-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) thiophene-2-carboxamide (Compound 8);
(S) -3-Chloro-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) thiophene-2-carboxamide (Compound 9);
(S) -3-Bromo-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) thiophene-2-carboxamide (Compound 10);
(S) -N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) furan-2-carboxamide (Compound 11);
(S) -N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) furan-3-carboxamide (Compound 12);
(S) -5-nitro-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) furan-2-carboxamide (Compound 13);
(S) -5-bromo-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) furan-2-carboxamide (Compound 14);
(S) -2-Methyl-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) furan-3-carboxamide (Compound 15);
(S) -4,5-dibromo-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) furan-2-carboxamide (Compound 16);
(S) -1H-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) pyrrole-2-carboxamide (Compound 17);
(S) -N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) pyridine-4-carboxamide (Compound 18);
(S) -6-chloro-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) pyridine-3-carboxamide (Compound 19);
(S) -4-fluoro-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) benzeneacetamide (Compound 20);
(S) -4-Chloro-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) benzeneacetamide (Compound 21);
(S) -4-Bromo-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) benzeneacetamide (Compound 22);
(S) -3-Fluoro-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) benzeneacetamide (Compound 23);
(S) -3-Chloro-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) benzeneacetamide (Compound 24);
(S) -3-Methyl-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) benzeneacetamide (Compound 25);
(S) -2-Trifluoromethyl-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) benzeneacetamide (Compound 26);
(S) -2-Fluoro-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) benzeneacetamide (Compound 27);
(S) -2-chloro-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) benzeneacetamide (Compound 28);
(S) -2-Bromo-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) benzeneacetamide (Compound 29);
(S) -2-Methyl-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) benzeneacetamide (Compound 30);
(S) -2-nitro-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) benzeneacetamide (Compound 31);
(S) -2,3-dichloro-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) benzeneacetamide (Compound 32); and

Selected from.

  In the second aspect, the present invention provides the homoserine lactone derivative according to the first aspect of the present invention, or its racemic or optical isomer, pharmaceutically acceptable salt, solvate, or hydrate. A method for the preparation of the following formula 3

(Wherein R is as defined in the first aspect of the present invention).
The homoserine lactone derivative according to the first embodiment of the present invention, or its racemic or optical isomer, pharmaceutically acceptable salt, solvate, is reacted with an acyl chloride represented by RCOCl. Or obtaining a hydrate.

  For the preparation method according to the second aspect of the present invention, the intermediate of formula 3 is prepared by reacting homoserine lactone hydrobromide with N-acetylsulfanilyl chloride. .

  In one embodiment of the present invention, the preparation method scheme is as follows:

(Wherein R is as defined in the first aspect of the present invention).
It is as follows.

  In a third aspect, the present invention provides a homoserine lactone derivative according to the first aspect of the present invention, or a racemic or optical isomer thereof, a pharmaceutically acceptable salt, a solvate, or a hydrate, And optionally a pharmaceutical composition comprising one or more pharmaceutically acceptable carriers or excipients.

  The pharmaceutical composition according to the third aspect of the present invention further contains at least one antibiotic.

  For the pharmaceutical composition according to the third aspect of the present invention, preferably the antibiotic includes, but is not limited to, β-lactam (eg, meropenem, cephalexin, ceftazidime, cefpirome, etc.) Aminoglycosides (eg, amikacin, streptomycin, tobramycin, isepamicin, etc.), glycopeptides (eg, vancomycin, teicoplanin, polymyxin, etc.), macrolides (eg, roxithromycin, clarithromycin, azithromycin, etc.), tetracyclines (eg, doxycycline, minocycline, etc.) Tigecycline, etc.), quinolones (eg, norfloxacin, ciprofloxacin, gatifloxacin, pazufloxacin, etc.), and the like.

  In a fourth aspect, the present invention relates to the homoserine lactone derivative according to the first aspect of the present invention or a racemic or optical isomer thereof, pharmaceutically acceptable, in the manufacture of a drug as a cell density sensing control agent. The use of a salt, solvate or hydrate.

  For the use according to the fourth aspect of the present invention, preferably the cell density sensing control agent may be a cell density sensing agonist or a cell density sensing inhibitor.

In some embodiments of the invention, the compound, or racemic or optical isomer, pharmaceutically acceptable salt, solvate, or hydrate thereof is used for the manufacture of a medicament as a cell density sensing agonist. May be used, where the compound is:
(S) -N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) furan-2-carboxamide (Compound 11);
(S) -2-fluoro-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) benzeneacetamide (Compound 27); and

Selected from the group consisting of

In some embodiments of the invention, the compound, or a racemate or optical isomer, pharmaceutically acceptable salt, solvate, or hydrate thereof, is used to produce a drug as a cell density sensing inhibitor. Wherein the compound is the following:
(S) -N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) thiophene-2-carboxamide (Compound 1);
(S) -N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) thiophene-3-carboxamide (Compound 2);
(S) -5-chloro-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) thiophene-2-carboxamide (Compound 3);
(S) -5-bromo-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) thiophene-2-carboxamide (Compound 4);
(S) -4-Bromo-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) thiophene-2-carboxamide (Compound 6);
(S) -4-Methyl-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) thiophene-2-carboxamide (Compound 7);
(S) -3-Methyl-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) thiophene-2-carboxamide (Compound 8);
(S) -3-Chloro-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) thiophene-2-carboxamide (Compound 9);
(S) -3-Bromo-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) thiophene-2-carboxamide (Compound 10);
(S) -N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) furan-2-carboxamide (Compound 11);
(S) -N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) furan-3-carboxamide (Compound 12);
(S) -5-nitro-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) furan-2-carboxamide (Compound 13);
(S) -2-Methyl-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) furan-3-carboxamide (Compound 15);
(S) -1H-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) pyrrole-2-carboxamide (Compound 17);
(S) -4-fluoro-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) benzeneacetamide (compound 20); and (S) -4-chloro-N- ( 4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) benzeneacetamide (Compound 21),
Selected from the group consisting of

  In a fifth aspect, the present invention relates to the homoserine lactone derivative according to the first aspect of the present invention or a racemic or optical product thereof in the manufacture of a medicament for the prevention and / or treatment of a disease caused by bacterial infection. It relates to the use of isomers, pharmaceutically acceptable salts, solvates or hydrates.

  For the use according to the fifth aspect of the invention, preferably the bacterium is a gram positive bacterium or a gram negative bacterium, preferably a gram negative bacterium.

  For the use according to the fifth aspect of the invention, preferably the gram-negative bacterium is E. coli, Bacillus pneumoniae, Bacillus proteus, dysentery. Bacillus dysenteriae, Brucella, Haemophilus influenzae, Hemofilus parainfluenzae, Moraxella catabarc. , Pasteurella la spp.), Shigella spp., Bordetella pertussis, Bordetella parapertussis, Vibrio Parahemiule, ELLIOLA V. cholera).

  For the use according to the fifth aspect of the present invention, preferably the diseases caused by the bacterial infection include, but are not limited to, various diseases such as endocarditis, peritonitis, Gastroenteritis, cholecystitis, cystitis, diarrhea, empyema, and sepsis, and the like; preferably the disease is caused by a drug resistant strain of bacteria that is not sensitive to antibiotics.

  In a sixth aspect, the present invention relates to the homoserine lactone derivative according to the first aspect of the present invention, or a racemic form thereof, in the manufacture of a medicament for the prevention and / or treatment of diseases caused by cell density sensing. It relates to the use of optical isomers, pharmaceutically acceptable salts, solvates or hydrates.

  For the use according to the sixth aspect of the present invention, preferably the diseases caused by cell density sensing include, but are not limited to, gram-negative bacteria such as E. coli, Bacillus pneumoniae, Bacillus proteus, Shigella, Brucella, Haemophilus influenzae, Parainfluenza, Moraxella catarrhalis, Acinetobacter, Yersinia, Pasteurella, Shigella, Bordetella pertussis, Parapertussis, Vibrio parahaemolyticus, Legionella pneumophila, and Various diseases caused by Vibrio cholerae are included, and the diseases caused by the Gram-negative bacteria include, but are not limited to, endocarditis, peritonitis, gastroenteritis, cholecystitis, bladder Including inflammation, diarrhea, empyema, septicemia; preferably the disease is an antibiotic Is a disease caused by drug-resistant strains of non-susceptible bacteria.

  In a seventh aspect, the present invention relates to the first aspect of the present invention as a tool drug for studying the cell density sensing control mechanism in vivo or in vitro. It relates to the use of the described homoserine lactone derivatives, or their racemates or optical isomers, pharmaceutically acceptable salts, solvates or hydrates.

  In an eighth aspect, the present invention provides a method for preventing and / or treating a disease caused by a bacterial infection, wherein the subject is in need of prevention and / or treatment of the disease. Administer a prophylactically and / or therapeutically effective amount of the homoserine lactone derivative according to the first aspect, or its racemic or optical isomer, pharmaceutically acceptable salt, solvate, or hydrate. It relates to a method comprising steps.

  For the method according to the eighth aspect of the invention, preferably the bacterium is a gram positive bacterium or a gram negative bacterium, preferably a gram negative bacterium.

  For the method according to the eighth aspect of the present invention, preferably the diseases caused by the bacteria include, but are not limited to, gram negative bacteria such as E. coli, Bacillus pneumoniae, Bacillus proteus. By Shigella, Brucella, Haemophilus influenzae, Parainfluenza, Moraxella catarrhalis, Acinetobacter, Yersinia, Pasteurella, Shigella, Bordetella pertussis, Vibrio parapertussis, Vibrio parahaemolyticus, Legionella pneumophila, and Vibrio cholerae The diseases caused by the gram-negative bacteria include, but are not limited to, endocarditis, peritonitis, gastroenteritis, cholecystitis, cystitis, diarrhea , Empyema, sepsis, etc .; preferably the disease is sensitive to antibiotics Is a disease caused by drug-resistant strains of no bacteria.

  In a ninth aspect, the present invention provides a method for preventing and / or treating a disease caused by cell density sensing, wherein the present invention is applied to a subject in need of prevention and / or treatment of the disease. A prophylactically and / or therapeutically effective amount of the homoserine lactone derivative according to the first aspect of the present invention, or a racemic or optical isomer, pharmaceutically acceptable salt, solvate or hydrate thereof. A method comprising the steps of:

  For the method according to the ninth aspect of the present invention, preferably the diseases caused by the cell density sensing include, but are not limited to, gram negative bacteria such as E. coli, Bacillus pneumoniae, Bacillus proteus, Shigella, Brucella, Haemophilus influenzae, Parainfluenza, Moraxella catarrhalis, Acinetobacter, Yersinia, Pasteurella, Shigella, Bordetella pertussis, Parapertussis, Vibrio parahaemolyticus, Legionella pneumophila, and Various diseases caused by Vibrio cholerae are included, and the diseases caused by the Gram-negative bacteria include, but are not limited to, endocarditis, peritonitis, gastroenteritis, cholecystitis, bladder Including inflammation, diarrhea, empyema, septicemia; preferably the disease is an antibiotic Is a disease caused by drug-resistant strains of non-susceptible bacteria.

  The present invention further relates to a method for studying the cell density sensing control mechanism in vivo or in vitro, wherein the homoserine lactone derivative according to the first aspect of the present invention or a racemic thereof is used as a tool drug. Or an optical isomer, a pharmaceutically acceptable salt, solvate, or hydrate.

  The present invention further provides the homoserine lactone derivative according to the first aspect of the present invention, or a racemic or optical form thereof, for use as a cell density sensing control agent (for example, a cell density sensing inhibitor or agonist). It relates to isomers, pharmaceutically acceptable salts, solvates, or hydrates.

  The present invention further provides the homoserine lactone derivative according to the first aspect of the present invention, or a racemic or optical isomer thereof, pharmaceutically, for use in the prevention and / or treatment of a disease caused by bacterial infection. It relates to acceptable salts, solvates or hydrates.

  In some embodiments of the invention, preferably the bacteria are gram positive or gram negative bacteria, preferably gram negative bacteria.

  In some embodiments of the present invention, preferably the gram negative bacterium is Escherichia coli, Bacillus pneumoniae, Bacillus proteus, Shigella, Brucella, Haemophilus influenzae, Parainfluenza, Moraxella catarrhalis, Acinetobacter Selected from the group consisting of Yersinia, Pasteurella, Shigella, Bordetella pertussis, Parapertussis, Vibrio parahaemolyticus, Legionella pneumophila, and Vibrio cholerae.

  In some embodiments of the invention, preferably the diseases caused by the bacterial infection include but are not limited to endocarditis, peritonitis, gastroenteritis, cholecystitis, cystitis, diarrhea, Includes empyema and sepsis.

  The present invention further provides the homoserine lactone derivative according to the first aspect of the present invention, or a racemic or optical isomer thereof, a pharmaceutical, for use in the prevention and / or treatment of a disease caused by cell density sensing. Permissible salts, solvates or hydrates.

  In some embodiments of the present invention, preferably the disease caused by the cell density sensing includes, but is not limited to, gram negative bacteria such as E. coli, Bacillus pneumoniae, Bacillus proteus, dysentery. Caused by Bacteria, Brucella, Haemophilus influenzae, Parainfluenza, Moraxella catarrhalis, Acinetobacter, Yersinia, Pasteurella, Shigella, Bordetella pertussis, Parapertussis, Vibrio parahaemolyticus, Legionella pneumophila, and Vibrio cholerae A variety of diseases, including, but not limited to, endocarditis, peritonitis, gastroenteritis, cholecystitis, cystitis, diarrhea, empyema Preferably, the disease is susceptible to antibiotics Is a disease caused by drug-resistant strains of no bacteria.

  The present invention further provides the homoserine lactone derivative according to the first aspect of the present invention, or a racemic thereof, for use as a tool drug for studying a cell density sensing control mechanism in vivo or in vitro. Or optical isomers, pharmaceutically acceptable salts, solvates, or hydrates.

DETAILED DESCRIPTION OF THE INVENTION The terms and phrases used in the present invention have general meanings well known to those skilled in the art, but are defined herein if they are specifically defined herein. The meaning shall prevail.

  As used herein, the term “heteroaryl” refers to a monocyclic heteroaromatic group and a polycyclic formed by condensing a monocyclic aromatic ring to one or more other aromatic rings. Refers to heteroaromatic groups containing 5-18 members, preferably 5-14 members, and more preferably 5-10 members, including heteroaromatic groups. Heteroaryl has one or more ring heteroatoms independently selected from the group consisting of N, O and S. As used herein, the term “heteroaryl” further results from the condensation of an aromatic ring to one or more non-aromatic rings (alicyclic rings or alicyclic hetero rings). Wherein the linking group or moiety is on the aromatic ring. Examples of “heteroaryl” include, but are not limited to, pyridyl, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, indolyl, benzofuranyl, benzimidazolyl, carbazolyl, pyridazinyl, pyrimidinyl , Pyrazinyl, quinolyl, isoquinolyl, guanine group, phenothiazinyl, phenoxazolyl and the like.

  As used herein, the term “halogen” has a general meaning well known in the art and generally includes F, Cl, Br, I, and isotopes thereof, and is preferably Is F, Cl or Br in the present invention.

As used herein, the term "C _{1 ~ 6} alkyl" includes straight-chain having 1 to 6 carbon atoms, branched, or refers to a cyclic alkyl include, but are not limited to, Including methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

  As used herein, the groups represented by the following terms: thienyl, furyl, pyrrolyl, pyridyl, benzyl, trifluoromethyl, nitro, and methyl have the general meanings well known in the art. Have.

  As used herein, the terms “racemate” and “optical isomer” have the general meaning well known in the art.

  According to the present invention, the subject is a mammal, such as a cow, horse, caprid, wild boar, canine, feline, rodent and primate; where a particularly preferred subject is a human.

  According to the present invention, the present invention relates to a suitable pharmaceutically acceptable salt or hydrate of a compound of formula I or an isomer thereof, wherein the pharmaceutically acceptable salt includes: Inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, phosphorous acid, hydrobromic acid, and nitric acid, and various organic acids such as maleic acid, malic acid, fumaric acid, succinic acid , Tartaric acid, citric acid, acetic acid, lactic acid, methanesulfonic acid, p-toluenesulfonic acid, and palmitic acid and salts formed from compounds of formula I. Some compounds of the present invention may be crystallized or recrystallized from water or various organic solvents. In this case, various solvates can be formed. The present invention includes stoichiometric solvates including hydrates, as well as compounds containing variable amounts of water prepared by drying methods using sublimation at low pressure.

  According to the invention, an isomer of a compound of formula I means that some compounds of the invention may exist in the form of optical isomers or tautomers. The present invention includes all existing forms, particularly in the form of pure isomers. Different forms of isomers may be separated or resolved from other forms of isomers by various conventional means, or certain isomers may be synthesized by various conventional synthetic methods, or stereospecific or asymmetric synthesis. It may be obtained by a method. Since the compounds of formula I are used for pharmaceutical purposes, they are most preferably in pure form, for example at least 60% purity, more preferably 75% purity, more preferably 85% purity, and It can be seen that it is most preferably provided with a purity of at least 98% (% means weight percent). Impure compounds can be applied to the preparation of compounds in purer form in pharmaceutical compositions. Impure products comprise at least 1%, more preferably 5%, more preferably 10% of a compound of formula I or a pharmaceutically acceptable derivative thereof.

  In accordance with the present invention, compounds of formula I can be prepared by the following exemplary and exemplary methods including the following steps.

  1) Add methionine to a mixed solution of water, 2-isopropanol and glacial acetic acid, mix uniformly, and follow the addition of bromoacetic acid. The mixture is heated to reflux for 2 hours. After cooling to room temperature, the mixture is concentrated to give a yellow oily liquid. A mixed solution of 2-isopropanol and toluene (1: 1 V / V) is then added and the resulting mixture is concentrated under reduced pressure to give an orange oily liquid. Dioxane and concentrated hydrochloric acid are added to the oily liquid. The resulting mixture is heated at 50 ° C. for 20 minutes and then the heater is removed. After stirring overnight at room temperature, the mixture is placed in an ice bath. A yellow solid precipitates and is subjected to suction filtration. Wash with 2-isopropanol until the filter cake is white to obtain intermediate 1.

  2) Dissolve intermediate 1 and triethanolamine in an ethanol solution. At 0 ° C., p-acetamidobenzenesulfonyl chloride is added in several portions. After stirring at room temperature overnight, the reaction is poured into ice water and subjected to strong stirring for 1 hour. The precipitated white solid is filtered and collected, washed with ice water, dried under vacuum, and recrystallized with ethanol to give a white solid (Intermediate 2).

  3) Under stirring, 6N HCl is added to the ethanol solution of Intermediate 2. After heating to reflux for 4 hours, the reaction mixture is concentrated under reduced pressure. The residue is dissolved in water and the pH is adjusted to 7-8 with aqueous ammonia. After stirring for 1 hour, the precipitated white solid is filtered and collected, washed with ice water, dried under vacuum, and recrystallized with ethanol to give a white solid (Intermediate 3).

  4) Put intermediate 3 in a three-necked flask and add triethanolamine. Acyl chloride (RCOCl) is added dropwise within 10 minutes in a 0 ° C. ice bath. The ice bath is removed and the mixture is stirred overnight at room temperature. The reaction system is subjected to suction filtration under reduced pressure the next day, and the filtrate is washed with water. A pale yellow solid precipitates in the organic phase and the precipitated solid is filtered and collected and dried under vacuum to give a pale yellow solid (compound of formula I).

  Wherein R is as defined in the first aspect of the invention.

  The invention further relates to pharmaceutical compositions comprising at least one compound of formula I and at least one pharmaceutically acceptable carrier or excipient. The compound of formula I or a pharmaceutically acceptable salt thereof can be used in the form of a pharmaceutical composition, alone or in combination with a pharmaceutically acceptable carrier or excipient. When the compound is used in the form of a pharmaceutical composition, a suitable dosage form or dosage form is generally that of the compound of formula I according to the invention, or a pharmaceutically acceptable salt or solvate thereof. Prepared from an effective amount and one or more pharmaceutically acceptable carriers or excipients. The process includes mixing, granulating, compressing or dissolving the components by suitable means.

  The pharmaceutical composition according to the present invention is prepared by the following methods: oral administration, spray inhalation, rectal administration, intranasal administration, vaginal administration, topical administration, parenteral administration, for example, subcutaneous, intravenous, intramuscular, intraperitoneal, medullary cavity. May be administered either by intraventricular, intraventricular, intrasternal or intracranial injection or injection, or administration based on a transplant reservoir, where oral administration, intramuscular injection, intraperitoneal administration, or intraventricular administration is preferred. .

  Pharmaceutically acceptable carriers contained in the pharmaceutical composition of the present invention include, but are not limited to, ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins such as human serum proteins. Interference substances such as phosphate, glycerol, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated plant fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, chloride Examples include sodium, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulosic materials, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, beeswax, lanocerin, and the like. In the pharmaceutical composition, the carrier is present in an amount of 1% to 98% by weight, generally about 80% by weight. For convenience of use, local anesthetics, preservatives, buffering agents and the like may be dissolved directly in the carrier.

  Oral preparations such as oral tablets and capsules are excipients such as binders such as syrup, gum arabic, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers such as lactose, sucrose, corn starch, calcium phosphate Sorbitol, sorbitol, and aminoacetic acid; lubricants such as magnesium stearate, talc, polyethylene glycol, and silica; disintegrants such as potato starch; or acceptable lubricant enhancers such as sodium lauryl sulfate. The tablets may be coated by methods well known in pharmacology.

  The pharmaceutical composition of the present invention in oral liquid form is a dry product supplemented to water and oil suspensions, solutions, emulsions, syrups or elixirs or supplemented with water or other suitable medium prior to use. May be prepared. Liquid formulations are conventional additives such as suspending agents, sorbitol, methylcellulose, glucose syrup, gel, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, hydrogenated edible fat, emulsifiers such as lecithin, mono Sorbitan oleate, gum arabic; or non-aqueous carriers (which may include edible oils) such as almond oil, fats such as glycerol, ethylene glycol or ethanol; preservatives such as methyl or propyl parahydroxybenzoic acid, sorbic acid Good. If necessary, a flavoring agent or a coloring agent may be added. Suppositories may contain conventional suppository bases such as cocoa butter or other glycerides. For parenteral administration, liquid dosage forms are generally prepared from the compound and at least one sterile or sterile carrier. The optimal carrier is water. Depending on the carrier selected and the concentration of the drug, the compound may be dissolved in the carrier or prepared in a suspension solution. When preparing injectable solutions, the compounds are first dissolved in water and packaged in sealed bottles or ampoules after filtration and sterilization. When administered topically to the skin, the compounds of the invention may be prepared in suitable forms of ointments, lotions or creams in which the active ingredient is suspended or dissolved in one or more carriers. Carriers for use in ointment formulations include, but are not limited to, mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; lotions and creams Carriers for use include, but are not limited to, mineral oil, sorbitan monostearate, Tween 60, hexadecyl ester wax, hexadecane aromatic alcohol, 2-octyldodecanol, benzyl alcohol and Contains water. Depending on the route of administration, the composition may contain 0.1% by weight of active ingredient, more preferably 10-60% by weight. However, when the composition is in unit dosage form, each unit optimally contains from 50 to 500 mg of active ingredient. Depending on the route of administration and frequency of administration, a suitable therapeutic dose for an adult is, for example, 100-3000 mg per day, for example 1500 mg per day.

  The optimal dosage and interval of the compound of Formula I will depend on the severity of the disease or disorder, the nature and condition of the compound, eg, the mode of administration, route and site, and the particular mammal to be treated. It should be recognized. The optimal dosage can be determined by a clinician.

Beneficial technical effects of the invention The present invention deprives pathogenic bacteria of pathogenicity by modulating the expression of pathogenic genes of pathogenic bacteria without interfering with the normal physiological functions of the cells, and thus antimicrobial agents A new series of cell density sensing and control agents, which are considered to be a new direction of development, are provided. Among these, cell density sensing inhibitors prevent and / or prevent various diseases caused by gram-negative bacteria such as endocarditis, peritonitis, gastroenteritis, cholecystitis, cystitis, diarrhea, empyema, and sepsis. Or can be used in combination with antibiotics to treat; and is particularly suitable for use in the prevention and / or treatment of diseases caused by drug-resistant gram-negative bacteria that are not sensitive to existing antibiotics.

Specific Modes for Carrying out the Invention The present invention is further illustrated by the following intermediates and examples. However, it should be understood that these intermediates and examples are only used to illustrate the invention in more detail and should not be construed as limiting the invention in any way.

  The present invention describes the materials and experimental methods used in the experiments in general and / or in detail. Although many materials and methods used to accomplish the objectives of the present invention are well known in the art, the present invention will be further described in as much detail as possible. Those skilled in the art know that the materials and methods used in the present invention are well known in the art unless otherwise stated.

In the following examples, the melting point of the compounds was measured with a YRT-4 type melting point apparatus where the temperature was not calibrated. The specific optical rotation was measured with a Polar 3005 Accuracy Automatic Polarimeter from OA Company. ¹ H-NMR spectra were measured with a Bruker ARX 400 type NMR spectrometer. The FAB mass spectrum was measured with a Zabbspect High Resolution mass spectrometer.

[Preparation of Intermediate]
[Preparation of Intermediate 1] (L) -homoserine lactone hydrobromide

20.0 g (134 mmol) L-methionine is added to a mixed solution of 80 ml water, 80 ml 2-isopropanol and 32 ml glacial acetic acid, mixed homogeneously, followed by addition of 18.8 g (134 mmol) bromoacetic acid. It was. The mixture was heated to reflux for 2 hours. After cooling to room temperature, the mixture was concentrated to give a yellow oily liquid. A mixed solution of 2-isopropanol and toluene (1: 1 V / V, 70 ml) was added to the resulting liquid. The resulting mixture was mixed and concentrated to give an orange oily liquid. 56 ml dioxane and 28 ml concentrated hydrochloric acid were added to the oily liquid. The resulting mixture was heated at 50 ° C. for 15 minutes and then the heater was removed. After stirring overnight at room temperature, the reaction was placed in an ice bath for 4 hours. A pale yellow solid was precipitated and suction filtered. The filter cake was washed with 2-isopropanol until white, yielding 10.9 g of product (Intermediate 1) in 45% yield.
1H-NMR (400MHz, D2O) δppm: 8.76 (s, 3H), 4.46 (t, 1H, J = 8.0 Hz, J = 7.6Hz), 4.35-4.31 (m, 2H), 2.56-2.51 (m, 1H ), 2.30-2.27 (m, 1H); EI-MS (m / z): 102.1 [M + H] +; mp220-224 ° C; [α] _D ²⁵ = -24.2 (c = 0.1, H2O).

[Preparation of Intermediate 2]
(S) -N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) acetamide

16.8 g (72 mmol) of p-acetamidobenzenesulfonyl chloride are combined with 10.9 g (60 mmol) of (L) -homoserine lactone hydrobromide (intermediate 1) and 25.5 mL (120 mmol) of triethanolamine. To a 120 mL ethanol solution at 0 ° C. in several portions. After stirring at room temperature overnight, the reaction was poured into ice water (200 mL) the next day and stirred for 1 hour. The precipitated white solid was filtered and collected, washed with ice water, dried under vacuum, and recrystallized with ethanol to give 12 g of white solid (Intermediate 2) in 67% yield.
1H-NMR (400MHz, DMSO) δppm: 10.33 (s, 1H), 8.16 (d, 1H, J = 8.0 Hz), 7.75 (s, 4H), 4.34-4.30 (m, 1H), 4.21 (m, 1H ), 4.08 (m, 1H), 2.08-2.06 (m, 4H), 1.80 (m, 1H); EI-MS (m / z): 299.34 [M + H] +; mp174-176 ° C.

[Preparation of Intermediate 3]
(S) -4-Amino-N- (2-oxotetrahydrofuran-3-yl) benzenesulfonamide

Under stirring, 20 mL of 6N HCl was added to 10 g (33 mmol) (s) -N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) acetamide in 40 mL ethanol solution. . After heating to reflux for 4 hours, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in water and the pH was adjusted to 7-8 with 1N aqueous ammonia. After stirring for 1 hour, the precipitated white solid was filtered and collected, washed with ice water, dried under vacuum and recrystallized with ethanol to give 5.2 g of white solid (Intermediate 3) 57% The yield was obtained.
1H-NMR (400MHz, DMSO) δppm: 7.72 (d, 1H, J = 9.2 Hz), 7.45 (d, 2H, J = 8.4 Hz), 6.61 (d, 2H, J = 8.8 Hz), 5.95 (m, 2H), 4.21 (m, 2H), 4.09 (m, 1H), 2.06 (m, 1H), 1.78 (m, 1H); EI-MS: m / z = 256.4 [M + H] +; mp162-165 ° C.

[Example]
[Example 1]
(S) -N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) thiophene-2-carboxamide (Compound 1)

0.52 g (2.03 mmol) of (s) -4-amino-N- (2-oxotetrahydrofuran-3-yl) benzenesulfonamide (intermediate 3) was placed in a three-necked flask containing 15 ml of anhydrous dichloromethane. .41 g (4.06 mmol) of triethanolamine was added. In a 0 ° C. ice bath, 0.36 g (2.44 mmol) of thiophene-2-carbonyl chloride is slowly added dropwise within 10 minutes. The ice bath was removed and the mixture was stirred overnight at room temperature. The reaction system was subjected to suction filtration under reduced pressure the next day, and the filtrate was washed with water. A pale yellow solid is precipitated in the organic phase, the precipitated solid is subjected to suction filtration under reduced pressure and dried under vacuum to give 0.44 g of a pale yellow solid (compound 1) in a yield of 60%. Got in.
1H-NMR (400MHz, DMSO) δppm: 10.57 (s, 1H), 8.25 (1H, d, J = 8.0 Hz), 8.22 (d, 1H, J = 8.0 Hz), 8.07 (d, 1H, J = 8.0 Hz), 7.93 (m, 3H), 7.82 (d, 2H, J = 8.0 Hz), 7.26 (d, 1H, J = 8.0 Hz), 4.37 (m, 1H), 4.23 (m, 1H), 4.11 ( m, 1H), 2.14 (m, 1H), 1.84 (m, 1H); EI-MS: m / z = 366.9 [M + H] +; mp114-119 ° C.

[Example 2]
(S) -N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) thiophene-3-carboxamide (Compound 2)

The intermediate 3 and thiophene-3-carbonyl chloride were used as raw materials and the operation was carried out as described in Example 1 to obtain a khaki solid product (Compound 2).
1H-NMR (400MHz, DMSO) δppm: 10.38 (s, 1H), 8.42 (1H, s), 8.20 (d, 1H, J = 8.0 Hz), 7.96 (d, 2H, J = 8.0 Hz), 7.82 ( m, 2H), 7.68 (d, 2H, J = 8.0 Hz), 4.37 (m, 1H), 4.23 (m, 1H), 4.11 (m, 1H), 2.14 (m, 1H), 1.83 (m, 1H ); EI-MS: m / z = 367.0 [M + H] +; mp212-216 ° C.

[Example 3]
(S) -5-Chloro-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) thiophene-2-carboxamide (Compound 3)

The intermediate 3 and 5-chloro-thiophene-2-carbonyl chloride were used as starting materials and the operation was performed as described in Example 1 to give an orange solid product (Compound 3).
1H-NMR (400MHz, DMSO) δppm: 10.64 (s, 1H), 8.21 (d, 1H, J = 8.0 Hz), 7.94 (m, 3H), 7.82 (d, 2H, J = 8.0 Hz), 7.32 ( s, 1H), 4.37 (m, 1H), 4.22 (m, 1H), 4.10 (m, 1H), 2.14 (m, 1H), 1.83 (m, 1H); EI-MS: m / z = 401.1 [ M + H] +; mp 243-249 ° C.

[Example 4]
(S) -5-Bromo-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) thiophene-2-carboxamide (Compound 4)

The intermediate 3 and 5-bromo-thiophene-2-carbonyl chloride were used as starting materials and the operation was performed as described in Example 1 to give an orange solid product (Compound 4).
1H-NMR (400MHz, DMSO) δppm: 10.63 (s, 1H), 8.21 (d, 1H, J = 8.0 Hz), 7.91 (m, 3H), 7.83 (d, 2H, J = 8.0 Hz), 7.40 ( s, 1H), 4.36 (m, 1H), 4.22 (m, 1H), 4.10 (m, 1H), 2.13 (m, 1H), 1.83 (m, 1H); EI-MS: m / z = 445.0 [ M + H] +; mp 197-199 ° C.

[Example 5]
(S) -5-Nitro-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) thiophene-2-carboxamide (Compound 5)

The intermediate 3 and 5-nitro-thiophene-2-carbonyl chloride were used as raw materials and the operation was performed as described in Example 1 to give a white solid product (Compound 5).
1H-NMR (400MHz, DMSO) δppm: 10.96 (s, 1H), 8.23 (d, 2H, J = 8.0 Hz), 8.10 (d, 1H, J = 8.0 Hz), 7.93 (m, 4H), 4.36 ( m, 1H), 4.21 (m, 1H), 4.09 (m, 1H), 2.13 (m, 1H), 1.83 (m, 1H); EI-MS: m / z = 434.2 [M + Na] +; mp208 -220 ° C.

[Example 6]
(S) -4-Bromo-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) thiophene-2-carboxamide (Compound 6)

The intermediate 3 and 4-bromo-thiophene-2-carbonyl chloride were used as starting materials and the operation was carried out as in Example 1 to give an orange solid product (Compound 6).
1H-NMR (400MHz, DMSO) δppm: 10.66 (s, 1H), 8.24 (d, 1H, J = 8.0 Hz), 8.12 (d, 2H, J = 8.0 Hz), 7.94 (m, 2H), 7.86 ( m, 2H), 4.38 (m, 1H), 4.23 (m, 1H), 4.11 (m, 1H), 2.14 (m, 1H), 1.84 (m, 1H); EI-MS: m / z = 445.0 [ M + H] +; mp 197-203 ° C.

[Example 7]
(S) -4-Methyl-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) thiophene-2-carboxamide (Compound 7)

The intermediate 3 and 4-methyl-thiophene-2-carbonyl chloride were used as raw materials and the operation was performed as described in Example 1 to give a pale yellow solid product (Compound 7).
1H-NMR (400MHz, DMSO) δppm: 10.50 (s, 1H), 8.23 (d, 1H, J = 8.0 Hz), 7.94 (m, 3H), 7.81 (d, 2H, J = 8.0 Hz), 7.51 ( d, 1H, J = 8.0 Hz), 4.37 (m, 1H), 4.23 (m, 1H), 4.11 (m, 1H), 2.14 (m, 1H), 1.83 (m, 1H); EI-MS (m / z): 381.1 [M + H] +; mp 187-188 ° C.

[Example 8]
(S) -3-Methyl-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) thiophene-2-carboxamide (Compound 8)

The intermediate 3 and 3-methyl-thiophene-2-carbonyl chloride were used as starting materials and the operation was performed as described in Example 1 to give a white solid product (Compound 8).
1H-NMR (400MHz, DMSO) δppm: 10.36 (s, 1H), 8.23 (d, 1H, J = 8.0 Hz), 7.88 (d, 2H, J = 8.0 Hz), 7.79 (d, 2H, J = 8.0 Hz), 7.72 (m, 1H), 7.06 (d, 1H, J = 8.0 Hz), 4.36 (m, 1H), 4.23 (m, 1H), 4.11 (m, 1H), 2.14 (m, 1H), 1.83 (m, 1H); EI-MS: m / z = 381.0 [M + H] +; mp 176-178 ° C.

[Example 9]
(S) -3-Chloro-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) thiophene-2-carboxamide (Compound 9)

The intermediate 3 and 3-chloro-thiophene-2-carbonyl chloride were used as raw materials and the operation was performed as described in Example 1 to give a pale yellow solid product (Compound 9).
1H-NMR (400MHz, DMSO) δppm: 10.63 (s, 1H), 8.23 (d, 1H, J = 8.0 Hz), 7.96 (m, 1H), 7.87 (d, 2H, J = 8.0 Hz), 7.82 ( d, 2H, J = 8.0 Hz), 7.24 (d, 1H, J = 8.0 Hz), 4.37 (m, 1H), 4.23 (m, 1H), 4.11 (m, 1H), 2.13 (m, 1H), 1.83 (m, 1H); EI-MS: m / z = 401.3 [M + H] +; mp 219-221 ° C.

[Example 10]
(S) -3-Bromo-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) thiophene-2-carboxamide (Compound 10)

The intermediate 3 and 3-chloro-thiophene-2-carbonyl chloride were used as raw materials and the operation was performed as described in Example 1 to give a pale yellow solid product (Compound 10).
1H-NMR (400MHz, DMSO) δppm: 10.71 (s, 1H), 8.24 (d, 1H, J = 8.0 Hz), 7.92 (m, 1H), 7.87 (d, 2H, J = 8.0 Hz), 7.83 ( d, 2H, J = 8.0 Hz), 7.27 (d, 1H, J = 8.0 Hz), 4.37 (m, 1H), 4.23 (m, 1H), 4.11 (m, 1H), 2.13 (m, 1H), 1.83 (m, 1H); EI-MS: m / z = 444.9 [M + H] +; mp 151-154 ° C.

[Example 11]
(S) -N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) furan-2-carboxamide (Compound 11)

The intermediate 3 and furan-2-carbonyl chloride were used as raw materials and the operation was performed as described in Example 1 to give an orange solid product (Compound 11).
1H-NMR (400MHz, DMSO) δppm: 10.49 (s, 1H), 8.18 (d, 1H, J = 8.0 Hz), 7.96 (m, 3H), 7.82 (d, 2H, J = 8.0 Hz), 7.40 ( d, 1H, J = 8.0 Hz), 6.72 (d, 1H, J = 8.0 Hz), 4.36 (m, 1H), 4.23 (m, 1H), 4.11 (m, 1H), 2.17 (m, 1H), 1.86 (m, 1H); EI-MS: m / z = 351.1 [M + H] +; mp 195-196 ° C.

[Example 12]
(S) -N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) furan-3-carboxamide (Compound 12)

The intermediate 3 and furan-3-carbonyl chloride were used as raw materials and the operation was performed as described in Example 1 to give a pale yellow solid product (Compound 12).
1H-NMR (400MHz, DMSO) δppm: 10.28 (s, 1H), 8.44 (s, 1H), 8.21 (d, 1H, J = 8.0 Hz), 7.92 (m, 5H), 7.02 (d, 1H, J = 8.0 Hz), 4.36 (m, 1H), 4.23 (m, 1H), 4.10 (m, 1H), 2.13 (m, 1H), 1.82 (m, 1H); EI-MS: m / z = 351.1 [ M + H] +; mp 202-209 ° C.

[Example 13]
(S) -5-Nitro-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) furan-2-carboxamide (Compound 13)

The intermediate 3 and 5-nitro-furan-2-carbonyl chloride were used as starting materials and the operation was performed as described in Example 1 to give a pale yellow solid product (Compound 13).
1H-NMR (400MHz, DMSO) δppm: 10.97 (s, 1H), 8.26 (d, 1H, J = 8.0 Hz), 7.95 (d, 2H, J = 8.0 Hz), 7.85 (m, 3H), 7.71 ( d, 1H, J = 8.0 Hz), 4.37 (m, 1H), 4.23 (m, 1H), 4.10 (m, 1H), 2.13 (m, 1H), 1.86 (m, 1H); EI-MS: m / z = 396.0 [M + H] +; mp113-120 ° C.

[Example 14]
(S) -5-Bromo-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) furan-2-carboxamide (Compound 14)

The intermediate 3 and 5-bromo-furan-2-carbonyl chloride were used as raw materials and the operation was performed as described in Example 1 to give a pale yellow solid product (Compound 14).
1H-NMR (400MHz, DMSO) δppm: 10.56 (s, 1H), 8.24 (d, 1H, J = 8.0 Hz), 7.94 (d, 2H, J = 8.0 Hz), 7.81 (d, 2H, J = 8.0 Hz), 7.45 (d, 1H, J = 8.0 Hz), 6.87 (d, 1H, J = 8.0 Hz), 4.36 (m, 1H), 4.23 (m, 1H), 4.10 (m, 1H), 2.13 ( m, 1H), 1.83 (m, 1H); EI-MS: m / z = 453.1 [M + Na] +; mp 190-196 ° C.

[Example 15]
(S) -2-Methyl-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) furan-3-carboxamide (Compound 15)

Intermediate 3 and 2-methyl-furan-3-carbonyl chloride were used as raw materials and the operation was performed as described in Example 1 to give a pale yellow solid product (Compound 15).
1H-NMR (400MHz, DMSO) δppm: 10.05 (s, 1H), 8.21 (d, 1H, J = 8.0 Hz), 7.94 (d, 2H, J = 8.0 Hz), 7.79 (d, 2H, J = 8.0 Hz), 7.63 (d, 1H, J = 8.0 Hz), 7.09 (d, 1H, J = 8.0 Hz), 4.36 (m, 1H), 4.23 (m, 1H), 4.11 (m, 1H), 2.53 ( s, 3H), 2.13 (m, 1H), 1.83 (m, 1H); EI-MS: m / z = 365.0 [M + H] +; mp 185-187 ° C.

[Example 16]
(S) -4,5-Dibromo-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) furan-2-carboxamide (Compound 16)

The intermediate 3 and 4,5-dibromo-furan-2-carbonyl chloride were used as starting materials and the operation was performed as described in Example 1 to give a pale yellow solid product (Compound 16).
1H-NMR (400MHz, DMSO) δppm: 10.66 (s, 1H), 8.23 (d, 1H, J = 8.0 Hz), 7.94 (d, 2H, J = 8.0 Hz), 7.82 (d, 2H, J = 8.0 Hz), 7.69 (d, 1H, J = 8.0 Hz), 4.36 (m, 1H), 4.23 (m, 1H), 4.11 (m, 1H), 2.14 (m, 1H), 1.85 (m, 1H); EI-MS: m / z = 529.0 [M + Na] +; mp 217-219 ° C.

[Example 17]
(S) -1H-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) pyrrole-2-carboxamide (Compound 17)

The intermediate 3 and pyrrole-2-carbonyl chloride were used as raw materials and the operation was performed as described in Example 1 to obtain a pale yellow solid product (Compound 17).
1H-NMR (400MHz, DMSO) δppm: 11.79 (d, 1H, J = 8.0 Hz), 10.10 (s, 1H), 8.17 (d, 1H, J = 8.0 Hz), 7.95 (d, 2H, J = 8.0 Hz), 7.80 (d, 2H, J = 8.0 Hz), 7.12 (d, 1H, J = 8.0 Hz), 7.02 (d, 1H, J = 8.0 Hz), 6.20 (d, 1H, J = 8.0 Hz) , 4.36 (m, 1H), 4.23 (m, 1H), 4.11 (m, 1H), 2.13 (m, 1H), 1.83 (m, 1H); EI-MS: m / z = 365.0 [M + H] +; mp170-174 ° C.

[Example 18]
(S) -N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) pyridine-4-carboxamide (7-19) (Compound 18)

The intermediate 3 and pyridine-4-carbonyl chloride were used as starting materials and the operation was performed as described in Example 1 to give a white solid product (Compound 18).
1H-NMR (400MHz, DMSO) δppm: 10.86 (s, 1H), 8.81 (m, 2H), 8.23 (d, 1H, J = 8.0 Hz), 7.97 (d, 2H, J = 8.0 Hz), 7.86 ( m, 4H), 4.36 (m, 1H), 4.23 (m, 1H), 4.11 (m, 1H), 2.14 (m, 1H), 1.83 (m, 1H); EI-MS: m / z = 362.1 [ M + H] +; mp 174-185 ° C.

[Example 19]
(S) -6-Chloro-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) pyridine-3-carboxamide (Compound 19)

The intermediate 3 and 6-chloro-pyridine-3-carbonyl chloride were used as raw materials and the operation was performed as described in Example 1 to give a pale yellow solid product (Compound 19).
1H-NMR (400MHz, DMSO) δppm: 10.85 (s, 1H), 8.96 (d, 1H, J = 8.0 Hz), 8.36 (d, 1H, J = 8.0 Hz), 8.25 (d, 1H, J = 8.0 Hz), 7.96 (d, 2H, J = 8.0 Hz), 7.85 (d, 2H, J = 8.0 Hz), 7.76 (d, 1H, J = 8.0 Hz), 4.38 (m, 1H), 4.23 (m, 1H), 4.09 (m, 1H), 2.14 (m, 1H), 1.83 (m, 1H); EI-MS: m / z = 396.1 [M + H] +; mp190-191 ° C.

[Example 20]
(S) -4-Fluoro-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) benzeneacetamide (Compound 20)

The intermediate 3 and 4-fluoro-phenylacetyl chloride were used as raw materials and the operation was performed as described in Example 1 to give a pale yellow solid product (Compound 20).
¹ H-NMR (400MHz, DMSO) δppm: 10.58 (s, 1H), 8.18 (d, 1H, J = 8.0 Hz), 7.77 (m, 4H), 7.36 (d, 2H, J = 8.0 Hz), 7.17 (dd, 2H, J = 8.0 Hz), 4.34 (m, 1H), 4.20 (m, 1H), 4.09 (m, 1H), 3.69 (s, 2H), 2.09 (m, 1H), 1.80 (m, EI-MS: m / z = 393.1 [M + H] +; mp 187-194 ° C.

[Example 21]
(S) -4-Chloro-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) benzeneacetamide (Compound 21)

Intermediate 3 and 4-chloro-phenylacetyl chloride were used as starting materials and the operation was performed as described in Example 1 to give a white solid product (Compound 21).
¹ H-NMR (400 MHz, DMSO) δ ppm: 10.57 (s, 1H), 8.16 (d, 1H, J = 8.0 Hz), 7.76 (m, 4H), 7.37 (m, 4H), 4.33 (m, 1H) , 4.21 (m, 1H), 4.09 (m, 1H), 3.70 (s, 2H), 2.10 (m, 1H), 1.80 (m, 1H); EI-MS: m / z = 409.2 [M + H] +; mp169-180 ° C.

[Example 22]
(S) -4-Bromo-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) benzeneacetamide (Compound 22)

The intermediate 3 and 4-bromo-phenylacetyl chloride were used as starting materials and the operation was performed as described in Example 1 to give a pale yellow solid product (Compound 22).
¹ H-NMR (400 MHz, DMSO) δ ppm: 10.57 (s, 1H), 8.16 (d, 1H, J = 8.0 Hz), 7.77 (m, 4H), 7.52 (d, 2H, J = 8.0 Hz), 7.29 (d, 2H, J = 8.0 Hz), 4.33 (m, 1H), 4.20 (m, 1H), 4.09 (m, 1H), 3.68 (s, 2H), 2.10 (m, 1H), 1.80 (m, 1H); EI-MS: m / z = 453.3 [M + H] +; mp 184-186 ° C.

[Example 23]
(S) -3-Fluoro-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) benzeneacetamide (Compound 23)

The intermediate 3 and 3-fluoro-phenylacetyl chloride were used as raw materials and the operation was performed as described in Example 1 to give a pale yellow solid product (Compound 23).
¹ H-NMR (400 MHz, DMSO) δ ppm: 10.58 (s, 1H), 8.16 (d, 1H, J = 8.0 Hz), 7.76 (m, 4H), 7.37 (m, 1H), 7.18 (m, 3H) , 4.32 (m, 1H), 4.21 (m, 1H), 4.09 (m, 1H), 3.73 (s, 2H), 2.10 (m, 1H), 1.80 (m, 1H); EI-MS: m / z = 393.2 [M + H] +; mp 175-177 ° C.

[Example 24]
(S) -3-Chloro-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) benzeneacetamide (Compound 24)

The intermediate 3 and 3-chloro-phenylacetyl chloride were used as raw materials and the operation was performed as described in Example 1 to give a white solid product (Compound 24).
¹ H-NMR (400 MHz, DMSO) δ ppm: 10.59 (s, 1H), 8.18 (d, 1H, J = 8.0 Hz), 7.76 (m, 4H), 7.37 (m, 4H), 4.33 (m, 1H) , 4.21 (m, 1H), 4.09 (m, 1H), 3.73 (s, 2H), 2.10 (m, 1H), 1.80 (m, 1H); EI-MS: m / z = 409.1 [M + H] +; mp188-190 ° C.

[Example 25]
(S) -3-Methyl-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) benzeneacetamide (Compound 25)

The intermediate 3 and 3-methyl-phenylacetyl chloride were used as raw materials and the operation was performed as described in Example 1 to give a white solid product (Compound 25).
¹ H-NMR (400MHz, DMSO) δppm: 10.58 (s, 1H), 8.18 (d, 1H, J = 8.0 Hz), 7.78 (m, 4H), 7.16 (m, 4H), 4.33 (m, 1H) , 4.20 (m, 1H), 4.08 (m, 1H), 3.73 (s, 2H), 2.11 (m, 1H), 1.80 (m, 1H); EI-MS: m / z = 389.1 [M + H] +; mp191-193 ° C.

[Example 26]
(S) -2-Trifluoromethyl-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) benzeneacetamide (Compound 26)

The intermediate 3 and 2-trifluoromethyl-phenylacetyl chloride were used as raw materials and the operation was performed as described in Example 1 to give a white solid product (Compound 26).
¹ H-NMR (400MHz, DMSO) δppm: 10.63 (s, 1H), 8.18 (d, 1H, J = 8.0 Hz), 7.74 (m, 6H), 7.53 (m, 2H), 4.33 (m, 1H) , 4.22 (m, 1H), 4.08 (m, 1H), 3.98 (s, 2H), 2.10 (m, 1H), 1.81 (m, 1H); EI-MS: m / z = 443.3 [M + H] +; mp197-198 ° C.

[Example 27]
(S) -2-Fluoro-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) benzeneacetamide (Compound 27)

The intermediate 3 and 2-fluoro-phenylacetyl chloride were used as raw materials and the operation was performed as described in Example 1 to give a white solid product (Compound 27).
¹ H-NMR (400 MHz, DMSO) δ ppm: 10.62 (s, 1H), 8.17 (d, 1H, J = 8.0 Hz), 7.76 (m, 4H), 7.19 (m, 4H), 4.32 (m, 1H) , 4.21 (m, 1H), 4.06 (m, 1H), 3.78 (s, 2H), 2.11 (m, 1H), 1.80 (m, 1H); EI-MS: m / z = 393.3 [M + H] +; mp185-186 ° C.

[Example 28]
(S) -2-Chloro-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) benzeneacetamide (Compound 28)

The intermediate 3 and 2-chloro-phenylacetyl chloride were used as raw materials and the operation was performed as described in Example 1 to give a white solid product (Compound 28).
¹ H-NMR (400MHz, DMSO) δppm: 10.64 (s, 1H), 8.18 (d, 1H, J = 8.0 Hz), 7.78 (m, 4H), 7.44 (m, 4H), 4.33 (m, 1H) , 4.21 (m, 1H), 4.08 (m, 1H), 3.89 (s, 2H), 2.11 (m, 1H), 1.81 (m, 1H); EI-MS: m / z = 409.2 [M + H] +; mp223-228 ° C.

[Example 29]
(S) -2-Bromo-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) benzeneacetamide (Compound 29)

The intermediate 3 and 2-bromo-phenylacetyl chloride were used as raw materials and the operation was performed as described in Example 1 to give a white solid product (Compound 29).
¹ H-NMR (400 MHz, DMSO) δ ppm: 10.65 (s, 1H), 8.18 (d, 1H, J = 8.0 Hz), 7.79 (m, 4H), 7.62 (d, 1H, J = 8.0 Hz), 7.42 (m, 2H), 7.22 (m, 1H), 4.34 (m, 1H), 4.22 (m, 1H), 4.08 (m, 1H), 3.91 (s, 2H), 2.13 (m, 1H), 1.83 ( m, 1H); EI-MS: m / z = 475.2 [M + Na] +; mp 227-229 ° C.

[Example 30]
(S) -2-Methyl-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) benzeneacetamide (Compound 30)

The intermediate 3 and 2-methyl-phenylacetyl chloride were used as raw materials and the operation was performed as described in Example 1 to give a white solid product (Compound 30).
¹ H-NMR (400 MHz, DMSO) δ ppm: 10.56 (s, 1H), 8.17 (d, 1H, J = 8.0 Hz), 7.78 (m, 4H), 7.16 (m, 4H), 4.35 (m, 1H) , 4.21 (m, 1H), 4.08 (m, 1H), 3.73 (s, 2H), 2.10 (m, 1H), 1.81 (m, 1H); EI-MS: m / z = 389.2 [M + H] +; mp208-210 ° C.

[Example 31]
(S) -2-Nitro-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) benzeneacetamide (Compound 31)

The intermediate 3 and 2-nitro-phenylacetyl chloride were used as raw materials and the operation was performed as described in Example 1 to give an orange solid product (Compound 31).
¹ H-NMR (400 MHz, DMSO) δ ppm: 10.66 (s, 1H), 8.18 (d, 1H, J = 8.0 Hz), 8.08 (d, 1H, J = 8.0 Hz), 7.75 (m, 5H), 7.59 (m, 2H), 4.34 (m, 1H), 4.21 (m, 1H), 4.18 (s, 2H), 4.08 (m, 1H), 2.11 (m, 1H), 1.81 (m, 1H); EI- MS: m / z = 420.4 [M + H] +; mp 216-219 ° C.

[Example 32]
(S) -2,3-Dichloro-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) benzeneacetamide (Compound 32)

Intermediate 3 and 2,3-dichloro-phenylacetyl chloride were used as starting materials and the operation was performed as described in Example 1 to give a pale yellow solid product (Compound 32).
¹ H-NMR (400MHz, DMSO) δppm: 10.67 (s, 1H), 8.17 (d, 1H, J = 8.0 Hz), 7.77 (m, 4H), 7.56 (d, 1H, J = 8.0 Hz), 7.36 (m, 2H), 4.34 (m, 1H), 4.20 (m, 1H), 4.08 (m, 1H), 3.97 (s, 2H), 2.11 (m, 1H), 1.81 (m, 1H); EI- MS: m / z = 443.3 [M + H] +; mp 230-237 ° C.

[Experimental Example] Evaluation of Activity of the Cell Density Sensing Control Agent of the Present Invention The activity of the cell density sensing control agent of the present invention can be measured by the following method.

1. Methods for preliminary screening 1.1 Preparatory work: Weigh the compounds to be tested (compounds 1-32 and intermediates 1-3 prepared in Examples 1-32) and then in 200 μl DMSO (dimethyl sulfoxide). Dissolved separately to prepare a solution at a concentration of 0.065M. N-hexanoyl homoserine lactone (C ₆ -HSL, purchased from Sigma Company), 5.0 mg inducer, was weighed and dissolved in 200 μl DMSO (at a concentration of 0.125 M), compound and inducer Were all stored at 4 ° C. for subsequent use. C. C. violaceum CV026 (provided by Prof. McLean JC of Texas State University, the bacterium is a Tn-5 mutant of wild-type Chromobacterium violaceum ATCC 31532; Latifif, A. et al. Mol. Microbiol, 17, 333-343 (1995) and Winson, M. K. et al., Proc. Natl. Acad. Sci. USA, 92, 9427-9431 (1995)) at 30 ° C., 200 rpm. And cultured with shaking on a shaker.

  1.2 Method for preliminary screening for compounds with agonist activity: 400 μl C.I. Violaceum CV026 was added to 5 ml of melted semi-solid LB medium (1% tryptone, 1% NaCl, and 0.5% yeast extract) and mixed evenly; the mixed medium was added to a solid LB plate. Poured; when mixed medium solidified on plate; 1 μl sample of dissolved compound to be tested (compounds 1-32 of Examples 1-32) was spotted on plate; once sample was dried in air, The plate was placed upside down in a 30 ° C. oven and incubated for 16-18 hours. The agonist activity of the compounds was determined on a LB plate by C.I. It was determined whether a purple strain was induced for Violaceum CV026 and the density of the purple strain.

1.3 Method for prescreening for compounds with inhibitory activity: Inducer C ₆ -HSL was serially diluted up to 1000-fold by 2-fold dilution; C.I in the log phase of 15 μl and 400 μl of diluted inducer. Violaceum CV026 was mixed evenly and then added to 5 ml of melted semi-solid LB medium; A mixture of violaceum and semi-solid LB medium was poured onto a solid LB plate; once the mixture solidified on the plate, the dissolved compounds to be tested (compounds 1-32 and Examples 1-3 of Examples 1-32) 1 μl of the sample was spotted on the plate; once the sample was dried in air, the plate was placed upside down in a 30 ° C. oven and incubated for 16-18 hours. The inhibitory activity of the compound was determined by C.I. Preliminary determination was made according to the size of the white circle appearing after Violaceum CV026 was inhibited on the LB plate.

  After preliminary screening, 17 compounds according to the present invention were found to have cell density sensing control activity, and the screening results are shown in Table 1.

2. C. Measurement of IC ₅₀ of compounds having an inhibitory effect on violaceum density sensing 2.1 The wells of a 12-well plate are divided into initial concentration groups, 2, 4, 8, 16, 32, 64, 128, and 256-fold dilution groups, The DMSO group and the blank control group were marked from left to right and top to bottom, respectively.

  2.2 Monoclonal C. grown on LB solid plates Violaceum CV026 was cultured to 5 logarithmic phase in 5 ml fresh LB liquid medium, then 50 μl was taken to inoculate 5 ml LB medium and cultured until the optical density OD value was about 1.0. The culture was then mixed uniformly with LB medium at a ratio of 1: 9 (at an OD of about 0.15) and added to a 12 well plate in an amount of 2 ml / well.

  2.3 Compounds with density sensing inhibitory activity in the preliminary screening were each dissolved in DMSO (at a concentration of 0.065 M), then 10 μl was placed in 10 μl DMSO solution for 2-fold dilution etc. Each compound was serially diluted up to 256-fold (2, 4, 8, 16, 32, 64, 128, 256-fold serial dilution).

2.4 To each well was added 15 μl of 1000-fold diluted inducer C ₆ -HSL (0.125 M initial concentration) and 8 μl of compound solution at each dilution step; for the DMSO group, 8 μl of DMSO was added. Added to the blank control group was 8 μl of LB medium. Finally, it was confirmed that 2 ml cultures of each of the 12 well plates were mixed uniformly.

  2.5 The 12-well plate was placed in a 30 ° C. shaker at 130 rpm and cultured for 10-12 hours.

2.6 After completion of the culture, 1 ml of culture was taken from each well, placed in a 1.5 ml EP tube, and then centrifuged at 12000 rpm for 10 minutes. The culture supernatant was aspirated and 500 μl DMSO was added to each EP tube to dissolve the purple dye in the culture. After complete dissolution of the dye, centrifugation was performed at 12000 rpm for 10 minutes. 200 μl of the supernatant dye was placed in a 96-well culture plate, and the absorbance value was measured at 585 nm with a microplate reader. Absorbance values and corresponding concentrations were plotted to obtain IC ₅₀ values. Specific results are shown in Table 2.

  In Table 1, “+” indicates that the compound has cell density sensing agonist activity, “−” indicates that the compound has cell density sensing inhibitory activity, and “±” indicates that the compound has cell density sensing activity. It represents having both agonist activity and inhibitory activity for sensing.

  While embodiments of the present invention have been described in detail, those skilled in the art can modify and replace these details in accordance with all previously disclosed teachings, and all of these changes are within the protection scope of the present invention. You will understand going into. The scope of the present invention is defined by the claims and any equivalents thereof.

Claims (19)

Formula I

Wherein R is a group selected from heteroaryl and benzyl, wherein
The heteroaryl is optionally halogen, trifluoromethyl, are nitro, and mono- or polysubstituted by substituents selected from the group consisting of C _{1 ~ 6} alkyl (e.g., disubstituted or trisubstituted); And
The benzyl is mono- or polysubstituted (eg, disubstituted or trisubstituted) with a substituent selected from the group consisting of halogen, trifluoromethyl, nitro, and C _1-6 alkyl
Homoserine lactone derivatives, or racemic or optical isomers, pharmaceutically acceptable salts, solvates, or hydrates thereof. R is a group selected from thienyl, furyl, pyrrolyl, pyridyl and benzyl, wherein
The thienyl, furyl, pyrrolyl, and pyridyl, optionally, halogen, trifluoromethyl, nitro, and mono- or polysubstituted by substituents selected from the group consisting of C _{1 ~ 6} alkyl (e.g., disubstituted or tri Replaced) ; and
The benzyl is mono- or polysubstituted (eg, disubstituted or trisubstituted) with a substituent selected from the group consisting of halogen, trifluoromethyl, nitro, and C _1-6 alkyl .
The homoserine lactone derivative according to claim 1, or a racemic or optical isomer, pharmaceutically acceptable salt, solvate or hydrate thereof.   R is thienyl, chlorothienyl, bromothienyl, nitrothienyl, methylthienyl, furyl, nitrofuryl, bromofuryl, methylfuryl, dibromofuryl, pyrrolyl, pyridyl, chloropyridyl, fluorobenzyl, chlorobenzyl, bromobenzyl, methylbenzyl, nitro The homoserine lactone derivative of claim 1, selected from the group consisting of benzyl, trifluoromethylbenzyl, and dichlorobenzyl, or a racemic or optical isomer thereof, a pharmaceutically acceptable salt, a solvate, or Hydrate. The homoserine lactone derivative is:
(S) -N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) thiophene-2-carboxamide (Compound 1);
(S) -N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) thiophene-3-carboxamide (Compound 2);
(S) -5-chloro-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) thiophene-2-carboxamide (Compound 3);
(S) -5-bromo-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) thiophene-2-carboxamide (Compound 4);
(S) -5-nitro-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) thiophene-2-carboxamide (Compound 5);
(S) -4-Bromo-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) thiophene-2-carboxamide (Compound 6);
(S) -4-Methyl-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) thiophene-2-carboxamide (Compound 7);
(S) -3-Methyl-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) thiophene-2-carboxamide (Compound 8);
(S) -3-Chloro-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) thiophene-2-carboxamide (Compound 9);
(S) -3-Bromo-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) thiophene-2-carboxamide (Compound 10);
(S) -N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) furan-2-carboxamide (Compound 11);
(S) -N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) furan-3-carboxamide (Compound 12);
(S) -5-nitro-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) furan-2-carboxamide (Compound 13);
(S) -5-bromo-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) furan-2-carboxamide (Compound 14);
(S) -2-Methyl-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) furan-3-carboxamide (Compound 15);
(S) -4,5-dibromo-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) furan-2-carboxamide (Compound 16);
(S) -1H-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) pyrrole-2-carboxamide (Compound 17);
(S) -N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) pyridine-4-carboxamide (Compound 18);
(S) -6-chloro-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) pyridine-3-carboxamide (Compound 19);
(S) -4-fluoro-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) benzeneacetamide (Compound 20);
(S) -4-Chloro-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) benzeneacetamide (Compound 21);
(S) -4-Bromo-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) benzeneacetamide (Compound 22);
(S) -3-Fluoro-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) benzeneacetamide (Compound 23);
(S) -3-Chloro-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) benzeneacetamide (Compound 24);
(S) -3-Methyl-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) benzeneacetamide (Compound 25);
(S) -2-Trifluoromethyl-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) benzeneacetamide (Compound 26);
(S) -2-Fluoro-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) benzeneacetamide (Compound 27);
(S) -2-chloro-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) benzeneacetamide (Compound 28);
(S) -2-Bromo-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) benzeneacetamide (Compound 29);
(S) -2-Methyl-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) benzeneacetamide (Compound 30);
(S) -2-nitro-N- (4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) benzeneacetamide (compound 31); and (S) -2,3-dichloro-N -(4- (N- (2-oxotetrahydrofuran-3-yl) sulfamoyl) phenyl)) benzeneacetamide (Compound 32);
The homoserine lactone derivative of formula I according to claim 1, or a racemic or optical isomer, pharmaceutically acceptable salt, solvate or hydrate thereof selected from: A homoserine lactone derivative of formula I according to any one of claims 1 to 4, or a racemic or optical isomer, pharmaceutically acceptable salt, solvate or hydrate thereof. A method comprising:

(Wherein R is as defined in any one of claims 1 to 4).
The intermediate of is reacted with an acyl chloride represented by RCOCl, the homoserine lactone derivative according to any one of claims 1 to 4, or a racemic or optical isomer thereof, a pharmaceutically acceptable salt, Obtaining a solvate or hydrate comprising a step.   6. The method of claim 5, wherein the intermediate of formula 3 is prepared by reacting homoserine lactone hydrobromide with acetylsulfanilyl chloride.   The homoserine lactone derivative according to any one of claims 1 to 4, or its racemate or optical isomer, pharmaceutically acceptable salt, solvate, or hydrate, and optionally one or more A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient.   8. The pharmaceutical composition according to claim 7, further comprising at least one antibiotic.   The homoserine lactone derivative according to any one of claims 1 to 4, or a racemic or optical isomer thereof, for use as a fungus density sensing control agent (for example, a fungus density sensing inhibitor or agonist). , A pharmaceutical composition containing a pharmaceutically acceptable salt, solvate or hydrate.   The homoserine lactone derivative according to any one of claims 1 to 4, or a racemic or optical isomer thereof, for use in prevention and / or treatment of a disease caused by bacterial infection. A pharmaceutical composition containing a salt, solvate or hydrate.   The pharmaceutical composition according to claim 10, wherein the bacterium is a gram positive bacterium or a gram negative bacterium.   The pharmaceutical composition according to claim 10, wherein the bacterium is a gram-negative bacterium.   The gram-negative bacterium is Escherichia coli, Bacillus pneumoniae, Bacillus proteus, Shigella, Brucella, Haemophilus influenzae, Parainfluenza, Moraxella catarrhalis, Acinetobacter, Yersinia, Pasteurella, Shigella, Bordetella pertussis, Para The pharmaceutical composition according to claim 11 or 12, selected from the group consisting of Bordetella pertussis, Vibrio parahaemolyticus, Legionella pneumophila, and Vibrio cholerae.   11. The pharmaceutical composition according to claim 10, wherein the disease caused by the bacterial infection is selected from endocarditis, peritonitis, gastroenteritis, cholecystitis, cystitis, diarrhea, empyema, and sepsis.   The homoserine lactone derivative according to any one of claims 1 to 4, or its racemic or optical isomer, pharmaceutically acceptable, for use in the prevention and / or treatment of a disease caused by cell density sensing A pharmaceutical composition containing a salt, solvate or hydrate.   Diseases caused by the cell density sensing are Gram-negative bacteria such as Escherichia coli, Bacillus pneumoniae, Bacillus proteus, Shigella, Brucella, Haemophilus influenzae, Parainfluenza, Moraxella catarrhalis, Acinetobacter, Yersinia, Pasteurella The pharmaceutical composition according to claim 15, which is a disease caused by a genus, Shigella, Pertussis, Parapertussis, Vibrio parahaemolyticus, Legionella pneumophila, or Vibrio cholerae.   17. The pharmaceutical composition according to claim 16, wherein the disease caused by the gram negative bacteria is selected from endocarditis, peritonitis, gastroenteritis, cholecystitis, cystitis, diarrhea, empyema, and sepsis.   The pharmaceutical composition according to claim 16 or 17, wherein the disease is caused by a drug-resistant strain of bacteria that is not sensitive to antibiotics.   The homoserine lactone derivative according to any one of claims 1 to 4, or a racemic form thereof, for use as a tool drug for studying a cell density sensing control mechanism in vivo or in vitro A pharmaceutical composition comprising an optical isomer, a pharmaceutically acceptable salt, a solvate, or a hydrate.